IRF8 and IRF3 cooperatively regulate rapid interferon-β induction in human blood monocytes
IRF8 and IRF3 cooperatively regulate rapid interferon-β induction in human blood monocytes
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DOI：
10.1182/blood-2010-07-294272
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发表时间：
2011-03-10
期刊：
影响因子：
20.3
通讯作者：
Chin, Keh-Chuang
中科院分区：
文献类型：
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作者：
Li, Peng;Wong, Joyce Jing-Yi;Chin, Keh-Chuang
在致病性刺激后，单核细胞中干扰素- β (ifn - β)的强劲和快速诱导是先天免疫反应的标志。在这里，我们揭示了人类血液单核细胞独有的这一关键特性的分子机制。我们发现，由于骨髓特异性转录因子IRF8和普遍存在的转录因子IRF3之间的合作，ifn - β在原代人单核细胞中迅速产生。在单核细胞中敲低IRF8可消除ifn - β转录，而在IRF8(-/-) 32Dcl3小鼠髓系中重新引入IRF8可恢复ifn - β转录。此外，我们提供的证据表明，IRF8在体内与PU.1一起组成性地结合到ifn - β启动子区域的ETS/IRF复合元件上。此外，我们发现了对IRF3的需求，IRF3是ifn - β产生的主要调节因子，是IRF8之前未确定的相互作用伙伴。我们绘制了IRF3和IRF8的蛋白-蛋白相互作用区域，发现它们的相互作用分别独立于IRF8和IRF3的dna结合域和IRF关联域。因此，我们提出了在单核细胞中快速诱导ifn - β的模型，其中IRF8和PU.1在ifn - β启动子上形成支架复合物，促进IRF3的募集，从而实现ifn - β的快速转录。[血液，2011;117(10):2847-2854]
Robust and rapid induction of interferon-beta (IFN-beta) in monocytes after pathogenic stimulation is a hallmark of innate immune responses. Here, we reveal the molecular mechanism underlying this key property that is exclusive to human blood monocytes. We found that IFN-beta was produced rapidly in primary human monocytes as a result of cooperation between the myeloid-specific transcription factor IRF8 and the ubiquitous transcription factor IRF3. Knockdown of IRF8 in monocytes abrogated IFN-beta transcription, whereas reintroduction of IRF8 into the IRF8(-/-) 32Dcl3 murine myeloid cell line reinstated IFN-beta transcription. Moreover, we provide evidence that IRF8 constitutively binds to the ETS/IRF composite element of the IFN-beta promoter region together with PU.1 in vivo. Furthermore we uncovered a requirement for IRF3, a master regulator of IFN-beta production, as a previously un-indentified interaction partner of IRF8. We mapped the protein-protein interacting regions of IRF3 and IRF8, and found that their interaction was independent of the DNA-binding domain and the IRF association domain of IRF8 and IRF3, respectively. Therefore, we propose a model for the rapid induction of IFN-beta in monocytes, whereby IRF8 and PU.1 form a scaffold complex on the IFN-beta promoter to facilitate the recruitment of IRF3, thus enabling rapid IFN-beta transcription. (Blood. 2011; 117(10): 2847-2854)